Nitrofen dose dependent and gestational day specific left-sided
diaphragmatic hernia and lung hypoplasia in fetal mice.
Cilley, Robert E., Steven E. Zgleszewski, Thomas M. Krummel, Mala R.
Chinoy.
Division of Pediatric Surgery, Department of Surgery, The
Pennsylvania State University College of Medicine, Milton S. Hershey
Medical Center, Hershey, PA 17033
APStracts 3:0165L, 1996.
Nitrofen (2,4-dichlorophenyl-p-nitrophenylether) has been known to
induce pulmonary hypoplasia with or without diaphragmatic hernias
(DH) in rats and mice. The purpose of our study was to determine the
timing of administration and dose of Nitrofen needed to create left
-sided DH and pulmonary hypoplasia in fetal mice. Time-dated pregnant
CD-1 mice (35g) were gavaged with various doses of Nitrofen (10mg to
35mg) on gestational days (Gd) 8-11. Fetuses were removed by
laparotomy at Gd 14, fixed and evaluated histologically, through
serial sectioning. Lungs were visibly smaller in a dose dependent
manner in the Nitrofen exposed fetuses. Morphometric analysis of
normal and Nitrofen exposed hypoplastic lungs using the Optimas Image
Analysis program revealed significant differences in lung size and
architecture. Serial sectioning of whole fetuses revealed left-sided
DH in a [circumflex]odorso-lateral[diaeresis]o position was
accompanied by pulmonary hypoplasia in Gd 14 fetuses from dams that
were gavaged with 25mg of Nitrofen at Gd 8. A minimal portion of
liver was present in the hernia, whereas intestine was not present in
the hernia at this stage of development when much of the intestine is
extra-coelomic. All fetuses without DH had hypoplastic lungs, when
exposed to Nitrofen at Gd 8. DH did not accompany pulmonary
hypoplasia in fetuses from maternal Nitrofen exposure on Gd 9 and 10,
and those from exposure on Gd 11 had no DH with near normal size
lungs. All the Nitrofen exposed fetuses had
[circumflex]ospongy[diaeresis]o bodies except the ones exposed on Gd
11, which had body walls with normal consistency. Our study
demonstrates that effects of Nitrofen on fetal lungs are dependent on
specific dose and time of gestation. Amongst the doses we evaluated,
it was clear that murine fetuses exposed to 25 mg of Nitrofen at Gd 8
resulted in PH and DH, whereas other doses created dose dependent PH
alone. Thus, our study establishes that the dose of Nitrofen and its
timing are crucial to create left-sided DH and pulmonary hypoplasia
in a murine model, as in the rat model.
Received 18 June 1996; accepted in final form 20 September 1996.
APS Manuscript Number L184-6.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996